Gene Therapy - Preventive Gene Therapy

Preventive Gene Therapy

Preventive gene therapy is the repair of a gene with a mutation associated with a progressive disease, prior to the expression of a medical condition, in order to prevent that expression. There are a number of considerations:

• It is hard to get U.S. FDA approval to treat a pre-symptomatic condition because it is hard to predict the complications that may arise, so it is hard to give a risk/benefit analysis. This is an obstacle to long-term therapies.
• It is easier to gain approval for short-term therapies to treat expressed conditions rather than prevent them.
• It is not known whether the repair of a mutation will help to treat a condition which has already progressed beyond the initial consequences of that mutation.

Similar to organ transplantation, gene therapy has been plagued by the problem of immune rejection. So far, delivery of the 'normal' gene has been difficult because the immune system recognizes the new gene as foreign and rejects the cells carrying it. To overcome this problem, the HSR-TIGET group utilized a newly uncovered network of genes regulated by molecules known as microRNAs. Dr. Naldini's group reasoned that they could use this natural function of microRNA to selectively turn off the identity of their therapeutic gene in cells of the immune system and prevent the gene from being found and destroyed. The researchers injected mice with the gene containing an immune-cell microRNA target sequence, and the mice did not reject the gene, as previously occurred when vectors without the microRNA target sequence were used. This work will have important implications for the treatment of hemophilia and other genetic diseases by gene therapy.

In November 2006 Preston Nix from the University of Pennsylvania School of Medicine reported on VRX496, a gene-based immunotherapy for the treatment of human immunodeficiency virus (HIV) that uses a lentiviral vector for delivery of an antisense gene against the HIV envelope. In the Phase I trial enrolling five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens, a single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was safe and well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. In addition, all five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in U.S. Food and Drug Administration-approved human clinical trials for any disease.